This invention relates to human complement Factor I and Factor H, both of which have now been found to be effective for the therapy of autoimmune diseases.
Antibody-antigen complexes are generated when antibodies bind to their specific alloantigens or autoantigens in vivo. Most of these complexes react with serum complement componets (C1, C4, C2 and C3), and thus so-called "immune complexes", consisting of antigen, antibody and the complement components including C3b, are generated. These immune complexes further interact with C5-C9 components, generating a membrane attack complex, C5b-C9, and an anaphylatoxin C5a, one of the most potent chemical mediators of inflammation. Moreover, such immune complexes are often deposited on the inside surfaces of blood vessels and also in the connective tissues around the vessels. These sequential events eventually cause inflammatory reactions and tissue damage.
On the other hand, there is a metabolic process for inactivating such active immune complexes. Factor I, one of the complement regulatory proteins, can inactivate C3b molecules in the immune complexes by converting the C3b to C3bi or C3d in co-operation with Factor H, C4b-binding protein and the complement receptors (CR1, CR2 and CR3) on erythrocytes and phagocytes. The immune complexes bearing such C3bi and C3d cannot further activate C5-C9 components and are eventually processed and cleared, mainly by the hepatic tissues. The level of immune complexes in the blood, therefore, is the result of a balance between the processes resulting in their generation and their inactivation (degradation).
Factors H and I and the ability of endogenous Factors H and I to inactivate C3b molecules in the normal course of the mammalian metabolism are known. Indeed, Factor I was hitherto known as "C3b inactivator" (="C3bINA") or "C4b inactivator" [see e.g. Hsiung et al. Biochem. J. (1982) 203, 293-298]. Factor H was hitherto known as ".beta.1H" [see e.g. Weiler et al. Proc. Natl. Acad. Sci. USA 73, 3268-3272 (1976)]. However, their value in the treatment of autoimmune diseases has not hitherto been suspected, nor has any casual connection between Factors H and I and such autoimmune diseases as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and glomerulonephritis been proved or suggested.
These autoimmune diseases, such as SLE, RA and glomerulonephritis, that are not effectively cured by current conventional therapy are considered to be vascular diseases, and we believe that they are mainly caused by the deposition of immune complexes inside and outside the blood vessels of various tissues, although the precise mechanism of the deposition of these immune complexes has not yet been elucidated. Recently, an inverse relationship between the frequency of occurrence of SLE and the genetically controlled density of complement receptor 1 (CR1) on erythrocytes (sites/cells) has been suggested. This also suggests that the occurrence and exacerbation of SLE is, at least in part, due to a reduced capability to process or inactivate the immune complexes. However, it is not possible to explain every such occurrence or exacerbation only by CR1 sites on erythrocytes, because
(1) about 40% of SLE patients have normal levels of CR1 sites
(2) about 12% of normal subjects have low levels of CR1 sites
(3) there are not differences in CR1 sites between the exacerbation and regression stages in the same SLE patients.
We have been searching for factors other than CR1 to correlate with the occurrence and exacerbation of SLE and have now found that the complement components Factor I and Factor H, both of which are essential for the inactivation of immune complexes, decreased in the preor early phases of the exacerbation stage, but not during most of the regression stage. This suggests that the temporary decrease in Factor I and/or Factor H may be one cause of the accumulation of immune complexes that exacerbate the clinical conditions of SLE patients.